N-alkylpiperidyl alkynylamines



United States Patent N-ALKYLPIPERIDYL ALKYNYLAMINES John H. Biel, Milwaukee, Wis, assignor to Lakeside Laboratories, Inc., a corporation of Wisconsin No Drawing. Original No. 2,867,620, dated January 6,

1959, Serial No. 606,977, August 30, 1956. Applicafion for reissue December 7, 1959, Serial No. 858,006

Claims. (Cl. 260-=247.5)

Matter enclosed in heavy brackets E] appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.

This invention relates to novel chemical compounds and processes of preparing the same, More particularly, this invention is concerned with novel derivatives of acetylene.

There is provided according to the present invention novel aminoalkynyl derivatives of N-alkylpiperidines of the formula and acid addition and quaternary ammonium salts thereof, wherein n is an integer from 1 through 6, n is an integer from 1 through 5, R is a lower alkyl group and R and R are the same or diflerent groups of the class consistingof lower alkyl groups, aryl groups, particularly monocyclic aryl groups such as the phenyl group, aralkyl groups, particularly monocyclic aryl-lower alkyl groups, and groups in which R and R are joined to form a ring, preferably a monocyclic ring with 5 or 6 atoms in the ring such as pyrrolidino, morpholino and piperidino. These compounds may be conveniently prepared by contacting a reactive metal salt of an aminoalkyne with an N-alkyl halopiperidine or an N-alkyl-piperidylalkyl halide. This reaction may be represented as follows:

wherein m, n, R, R and R have the significance previously assigned, X is a reactive halogen, and A is a reactive metal;

Representative N-alkyl halopiperidines and N-alkyl-piperidylalkyl halides which may be used in the process are N-methyl-3-chloropiperidine, N-propyl-4-bromopiperidine, N-methy1-3-bromoethylpiperidine, N-ethyl-4-chlorobutyl-piperidine and the like.

Typical aminoalkynes which may be used in the form.

the reflux temperature are suitable for effecting the reac- 2 tion. The reaction is terminated when essentially completed, which may take from about 1 to 20 hours, and the product recovered by conventional means from the reaction mixture.

Among the products which may be produced in this way from appropriate reactants are fi-(3-diethylamino-lpropynyl) N methyl piperidine, 8 (4 morpholino-2- butynyl) N methyl piperidine, 18 (3 dimethylamino- 1-propynyl)-N-methyl piperidine and 'y-(fi-pyrrolidino- 3-heXynyl)-N-propyl piperidine.

Acid addition salts of the compounds provided by this invention are formed by contacting one moleof the base with one to two moles of an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as maleic acid, fumaric acid, formic acid and citric acid.

Quaternary ammonium salts are produced by react ing the bases with alkyl, aralkyl, substituted aralkyl or alkynyl esters of inorganic and. organic acids. The reaction preferably is effected in the presence of a suitable inert organic solvent. Methyl bromide, propargyl bromide, o-chlorobenzyl iodide, methyl chloride, benzyl chloride and methyl sulfate are representative compounds that may be used .to form quarternary ammonium salts.

The non-toxic acid addition salts of the N-alkyl-piperidylalkynylamines are useful as diuretic agents in the treatment of congestive heart failure. The non-toxic quaternary ammonium salts are potent and long-acting hypotensive agents useful in the therapy of high blood pressure and peripheral vascular disease.

The following examples are presented to show methods of producing certain of the novel compounds included within this invention. It is understood, however, that these examples are included only for purposes of illustration, and that the invention is not to be restricted to the embodiments specifically disclosed therein.

EXAMPLE 1 B-(3-diethylam ino-l propynyl)-N-methyl piperidine To 12 gm. (0.3 mole) of sodarnide in 50 cc. of xylene was added 33 gm. (0.3 mole) of diethylaminopropyne. The mixture was heated at reflux for 1 hour and then 70 gm. (0.5 mole) of N-methyl-3-chloropiperidine was added. The mixture was refluxed for 20 hours. One hundred cc. of water was added to dissolve solids and the layers separated. The xylene layer was extracted three times with 150 cc. portions of dilute hydrochloric acid. The acid aqueous solution was washed three times with 50 cc. portions of ethyl ether, saturated with potassium hydroxide, and extracted three times with 150 cc. of ethyl ether. It was dried over potassium carbonate and the product recovered by vacuum distillation, B.P. 86-88 C./0.05 mm.; yield 80 gm., 77%.

EXAMPLE 2 ,B-(4-morpholino-2-butynyl)-N1methy1 piperidine To 12 gm. (0.03 mole) of sodamide in cc. of toluene was added 38 gm. (0.3 mole) of morpholino propyne. It was refluxed for 1 hour and 89 gm. of N-methyl-3- bromomethyl piperidine added. After refluxing for 20 hours the product was recovered asin Example 1, B.P. 107-110" C./0.07 mm.; yield 17 got, 34%.

Analysis.Calcd. C H N O: 11.86% N. Found: 11.81% N.

N. Found:

EXAMPLE 3 ,8-(3-dimethylamino-1-propynyl)-N-methyl piperidine Sodium dimethylaminopropyne was reacted with N- rnethyl-S-chloropiperidine as in Example 1 to form this compound, B.P. 70-73 C./ 1.5 mm.

Analysis.-Calcd. 15.55% N. Found: 15.01% N.

3 EXAMRLE 4 fi-(B-pyrrolidino-l-propynyl)-N-mcthyl pipcridine.

Sodium pyrrolidino propyne was reacted with N- methyl-3-chloropiperidine as in Example 1, B.P. 107- 109 C./0.05 mm. 7

Analysis.--Calcd.: 13.59% N. Found:

Sodium diethylamino propyne and N-methyl-B-bromy methyl piperidine were reacted as in. Example 1 to form thisbase; B.P. 88-90 C./0.3 mm.

Analysis.-Calcd.: 12.61% N. Found: 12.24% N.

' EXAMPLE 7 fi-(4-pyrrolidino-1-butynyl)-N-methyl piperidine Sodium pyrrolidino propyne and N-methyl-B-bromomethyl piperidine when reacted as in Example 1 gave this compound; B.P. 95-98 C./0.5 mm.

Analysis.Ca1cd.: 12.72% N. Found: 12.32% N.

EXAMPLE 8 fl-(3-dimethylamino-l-propynyl)-N-methyl piperidine bis-hydrochloride To 9 gm. (0.05 mole) of the base from Example 3 in 0 cc. of acetone was added ethyl ether and hydrochloric acid to pH 2-3. It was refrigerated overnight, filtered and dried, M.P. 193-194 C.

Analysis.-Calcd. C H N Cl 11.06% N, 28.06% Cl. Found: 10.98% N, 26.92%v Cl.

EXAMPLE 9 p-(3-dimethy1arnino-1-propynyl) -N-methylpiperidine bis-methobromide To. 18 gm. (0.1 mole) of the base from Example 3 4 What is claimed is: 1. Di-lower alkyl-amino-lower alkynyl-N-lower alkyl piperidine.

2. p-(S-diethylamino-l-propynyl)-N-methy1 piperidinc. 3. p-(4-morpholino-2-butynyl)-N-methyl piperidine. 4. B-(B-dimethylamino-l-propynyl) -N methyl piperidine.

5. p-(3-pyrrolidino-l-propynyl)-N-methyl piperidine. 6. p-(3-morpholino-1-propyny1)-N-methy1 piperidine. 7. fl-(4-diethylamino-1-butynyl)-N-methyl piperidine. 8. fl-(4-pyrrolidino1-butynyl) -N-methyl piperidine. 9. A member of the group consisting of compounds of the formulae R1 (0Hflm-1C C-(CH2)n-N\ and non-toxic acid addition and non-toxic quaternary ammonium salts thereof, wherein m is an integer from 1 through 6, n is an integer from 1 through 5, R is a lower alkyl group and R and R are members of the group consisting of lower alkyl groups, and. groups in which represents a member of the group consisting of the morpholino, pyrrolidino and piperidino groups, said.

quaternary salts containing a member of the group consisting of lower alkyl, lower alkynyl and phenyl-lower alkyl groups.

10. The process which comprises reacting a member of the group consisting of compounds of the formulae in 50 cc. isopropanol was added 19 gm. (0.2 mole) of (CH2) methylbromide. The mixture was allowed to stand at room temperature overnight, filtered and the product dried, M.P. 212-213" C. l V I Analysis.-Calcd. CBHQQNQBI'QZ N, Br. Found: 7.45% N, 42.95% Br. N The following salts were also prepared:

, 7 and (CH6) m-GEG (CHflnAmnW'X l nker-X .RFX? 43H. 7 f and R Assay M .P Yield, Calcd Found Am m n B: X degrees percent Per- Per- Per- Per cent cent cent cent N x N x (01Hl) :I- I- 0 1 0H,- Br 214? 16 44 7.04 40.20 6.95 40. 71 Pwrohdrno--. 0 1 0H, Br 229- 30 66 7.07 40. 40 6.50 40.96 Morphollnon 0 1 CHs- Br 212- 13 86 6. 79 38.83 6.67 38.74 H5)1N- 0 1 HCEOOH: Br 80 92 6. 28 35.87 6.16 35.48 (OIHQ)B N 1 1 Hr- B1 155- 59 69 6.79 38.83 6. 43 36.44 Pyrrohdhm" 1 1 0H,- Br -102 85 6. s2, 39. 02 6. 55 36.41 Morpholmo-- 1 1 0 Br 232- as 66 6. 57 36.68 6. 26' 36.23

5 with e compound of the iorznuie s-cac-(cm -rs to produce the corresponding member of the group 901leisting of compounds of the formulae 31 o wmm-czcqcmn-n 6 wherein, in each occurrence, m is an integer from 1 through 6, n is an integer from 1 through 5, R is a lower alkyl group and R and R, are members of the group consisting of lower alkyl groups, and groups in which R1 represents a member of the group consisting of the morpholino, pyrrolidino and piperidino groups, X is a reacrive halogen and A is a reactive alkali metal.

References Cited in the file of this patent or the original patent UNITED STATES PATENTS 2,684,965 Weston et a1. July 27, 1954 2,771,391 Bockstahler Nov. 20, 1956 OTHER REFERENCES Profit: Chemische Technik, Die (Berlin), vol. 5, pp. 13-11 (1953). 

